Synthesis and Isomerization of the 2-Methyl Enal Fragment of Acyclic Precursors to 9,11-Diene Analogs of Epothilones
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hesis and Isomerization of the 2-Methyl Enal Fragment of Acyclic Precursors to 9,11-Diene Analogs of Epothilones R. F. Valeeva,*, G. R. Sunagatullinaa, and M. S. Miftakhova a
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, Ufa, 450054 Russia *e-mail: [email protected] Received February 20, 2020; revised March 26, 2020; accepted March 30, 2020
Abstract—Yamaguchi esterification of (2Z,5S,6E)-5-(hydroxymethyl)-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4yl)hepta-2,6-dienal with (2R,5R,6S,7S)-2-(methoxymethoxy)-3,3,5,7-tetramethyl-4-oxo-9-[(1-phenyl-1Htetrazol-5-yl)sulfonyl-6-[(triethylsilyl)oxy]nonanoic acid afforded the expected acyclic ester. Acid- and basecatalyzed Z,E-isomerization in the 2-methyl enal fragment of acyclic precursors was revealed. Keywords: Yamaguchi esterification, Julia–Kocienski reaction, 2-methyl enal, isomerization, epothilone D analogs
DOI: 10.1134/S1070428020070039 Synthesis and study of the properties of modified epothilones is a promising line of research in the field of design of effective anticancer agents [1]. In continuation of our studies on the synthesis of a new diene analog of epothilone D (1) [2], herein we report the results of our efforts aimed at obtaining compound 1 through acyclic building block 2, followed by intramolecular Julia–Kocienski (JK) cyclization [3] (Scheme 1). In turn, we planned to synthesize compound 2 via Yamaguchi esterification [4] of hydroxy aldehyde 3 with phenyltetrazolesulfonyl-substituted acid 4 [5]. In testing approaches to aldehyde component
3, previously synthesized TBS-protected alcohol 5 [6] was oxidized to expected enal 6 with the system PhI(OAc)2–TEMPO (Scheme 2). However, the subsequent deprotection of the hydroxy group in 6 by the action of p-toluenesulfonic acid in methanol–methylene chloride was accompanied by isomerization of the cis-C2=C 3 double bond. By column chromatography on silica gel we isolated trans-enal 7 and intermediate enol which was tentatively assigned structure 8. Presumably, some stabilization of the enol structure via hydrogen bonding is possible in this case. Compound 8 was completely
Scheme 1. Me S
Me S
Me
Me N
O
Me Me Me
O
Me
CHO
Me
OH
N
O
Me Me Me
O
Me OH
SO2PT
O
MeO
1 (Epothilone D analog)
Me O
O
2 Me
O Me
Me Me
Me
HO MOMO
S SO2PT
O
+
Me
CHO
Me N
OTES OH 4
3
1140
OTES
1141
SYNTHESIS AND ISOMERIZATION OF THE 2-METHYL ENAL FRAGMENT Scheme 2. CHO S
ii or iii
Me
Me
MeO OH
H
7
OH
Me
7
O O
Me
iv
N
+
Me N
S
Me
Me
Me
S
8
Me N OTBS
Me
Me
5 i
S
Me
Me CHO
Me
S
v
N
O 7 + Me
OTBS
N
OMe MeO
6
9
Reagents and conditions: i: TEMPO, PhI(OAc)2, CH2Cl2, 92%; ii:, TsOH, MeOH–CH2Cl2 (1:1); iii: TBAF, THF; iv: CHCl3, 48 h; v: Amberlyst®, MeOH.
converted to trans-enal 7 after keeping in chloroform for 48 h. Obviously, this reaction is catalyzed by traces of HCl present in chloroform. Similar result was obtained when compound 6 was treated with tetrabutylammonium fluoride. When Amberlyst® (ion exchange resin) in methanol was used, w
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